15 ketoprogesterones



15 KETOPROGESTERONES Josef Fried, New Brunswick, Richard W. Thoma,Somerville, David Perlman, Princeton, and John R. Gerke, FranklinTownship, N.J., assignors to Olin Mathieson Chemical Corporation, NewYork, N.Y., a corporation of Virginia No Drawing. Application May 27,1955 Serial No. 511,782

2 Claims. (Cl. 260397.3)

This application is a continuation-in-part of our copending application,Serial Number 372,798, filed August 6, 1953, now Patent No. 2,753,290,granted July 3, 1956.

This invention relates to the synthesis of valuable steroids.

One object of this invention is the provision of steroids of thepregnane (including the A -pregnene and the A 14-iso-17-isopregnene)series having a 15-keto group, which compounds are useful either fortheir own physiological action or as intermediates in the preparation ofphysiologically active derivatives.

The compounds of this invention comprise 15-ketoprogesterone and15-keto-14-iso-17-isoprogesterone. The preparation of the15-ketoprogesterone of this invention by the oxidation of15-hydroxyprogesterone is disclosed in our copending application, SerialNumber 372,798. filed August 6, 1953, now patent No. 2,753,290, grantedJuly 3, 1956. The 15-keto-14-iso-l7-isoprogesterone of this invention isprepared by isomerization of 15-ketoprogesterone.

To prepare the l-ketoprogesterone of this invention, eitherISa-hydroxyprogesterone or 15/3-hydroxyprogesterone is oxidized. Toeffect this oxidation, the 15- hydroxy steroid is treated with anoxidizing agent such as a hexavalent chromium (chromic) ion, e.g.chromic oxide, preferably in an organic acid medium (e. g. glacialacetic acid). The 1S-keto-14-iso-17-isoprogesterone of this invention isprepared by isomerizing 15-ketoprogesterone. This isomerization can beeffected by treating the 15-ketoprogesterone with a base, such as analkali (e.g. potassium hydroxide). The reaction can be conducted ineither an aqueous or organic solution but is preferably carried out inan organic solvent wherein both the IS-ketoprogesterone and the base aresoluble. Examples of such solvents are the lower alkanols (e.g.,methanol and ethanol).

The 15-ketoprogesterone of this invention is an active material whichpossesses progestational activity, and thus can be administered insteadof, and in the same manner as, progesterone in the treatment offunctional uterine bleeding and amenorrhea. The 15-keto-14-iso-17-isoprogesterone of this invention is also an active material whichpossesses androgenic activity and thus can be administered instead of,and in the same manner as, testosterone propionate in the treatment ofeunuchoidism or hypogonadism.

The following examples are illustrative of the invention (alltemperatures being in centigrade):

EXAMPLE 1 Oxidation of the 15u-hydroxypr0gesterone to 15-ketoprogesterone To a solution of 20 mg. of 15m-hydroxyprogesterone in 2ml. of glacial acetic acid is added a solution of mg. of chromic acid in2 ml. acetic acid. One hour later, 0.2 ml. of alcohol is added; andafter an additional 10 minutes the solution is evaporated to smallvolume in vacuo. The residue is taken up in little water, and exfittesPatent Patented Mar. 24, 1959 Oxidation of ISB-hydroxyprogesterone to15- ketoprogesterone The oxidation of 22 mg. of 15 3-hydroxyprogesteroneis conducted as described for the 15a-hydroxyprogesterone in Example 1.The recrystallized product has the following properties: lVLP. about159-160", [411 +200 (c., 0.49 in CHC1 The infrared spectrum is identicalwith that of the product obtained in Example 1, and the melting point ofa mixture of the two products shows no depression.

EXAMPLE 3 Isomerization of JS-ketoprogesterone t0 IS-keto- 14-is0-17-isoprogestemne To a solution of 51 mg. of IS-ketoprogesterone in 5 ml.of methyl alcohol is added 0.2 ml. of 1.35 N methanolic potassiumhydroxide. isomerization occurs rapid- 1y as evidenced by the rapid dropin specific rotation from an initial value of to an equilibrium value of126 after 2 hours. The solution is diluted with water and the methanoltaken off in vacuo. Chloroform is added and the chloroform extractwashed with dilute sodium bicarbonate solution, and with water. Afterdrying over sodium sulfate and evaporation of the solvent in vacuo, acrystalline residue results which is purified by chromatography onsilica gel. Elution of the column with 10% chloroform-benzene (600 ml.),25% chloroform-benzene (500 ml.) and 50% chloroform-benzene (700 ml.)affords crystalline material representing15-keto-14-iso-17isoprogesterone which after recrystallization fromacetone-hexane has the following properties: MJP. about 211-213"; [ch+l13 (c., 0.65 in chloroform); Mfg; 239 mn(e=17,900); x5 35.77;;(15-keto); 5.86 (20-keto), 6.00, 6.19;l(A-3-keto).

Analysis.Calcd. for C i-1 0 (328.43): C, 76.79; H, 8.59. C, 76.53; H,8.72.

15-keto-14-iso-l7-isoprogesterone can also be termed 15-keto-148,Una-progesterone and can be represented by the formula 5.77p.(15-k8l70); 5.891s

The invention may be otherwise variously embodied within the scope ofthe appended claims.

We claim:

!. 15-ketoprogesterone.

2. 1S-keto-14-iso-17-isoprogesterone.

No references cited.

1. 15-KETOPROGESTERONE.